Biomedical subjects

Eun-Jin Yeo

Publications and source records attributed to Eun-Jin Yeo.

9 recordsLinked to original sources

PubMed2006

YC-1 induces S cell cycle arrest and apoptosis by activating checkpoint kinases.

Hypoxia-inducible factor-1alpha (HIF-1alpha) seems central to tumor growth and progression because it up-regulates genes essential for angiogenesis and the hypoxic adaptation of cancer cells, which is why HIF-1alpha inhibition is viewed as a cancer therapy strategy. Paradoxically, HIF-1alpha also leads to cell cycle arrest or the apoptosis of cancer cells. Thus, the possibility cannot be ruled out that HIF-1alpha inhibitors unlock cell cycle arrest under hypoxic conditions and prevent cell death, which would limit the anticancer effect of HIF-1alpha inhibitors. Previously, we reported on the development of YC-1 as an anticancer agent that inhibits HIF-1alpha. In the present study, we evaluated the effects of YC-1 on hypoxia-induced cell cycle arrest and cell death. It was found that YC-1 does not reverse the antiproliferative effect of hypoxia, but rather that it induces S-phase arrest and apoptosis at therapeutic concentrations that inhibit HIF-1alpha and tumor growth; however, YC-1 did not stimulate cyclic guanosine 3',5'-monophosphate production in this concentration range. It was also found that YC-1 activates the checkpoint kinase-mediated intra-S-phase checkpoint, independently of ataxia-telangiectasia mutated kinase or ataxia-telangiectasia mutated and Rad3-related kinase. These results imply that YC-1 does not promote the regrowth of hypoxic tumors because of its cell cycle arrest effect. Furthermore, YC-1 may induce the combined anticancer effects of HIF-1alpha inhibition and cell growth inhibition.

Apoptosis↗

PubMed2006

FK506: an immunosuppressive agent preserving HIF-1 activity.

During transplantation, donor organs or cells are subjected to hypoxia. Hypoxia-inducible factor-1 (HIF-1) is essential for cellular adaptation to hypoxia. Immunosuppressive agents should be used for preventing graft rejection, but of these, rapamycin and cyclosporine A have been reported to inhibit HIF-1. We examined whether or not another important immunosuppressant, FK506, inhibits HIF-1. In contrast to cyclosporine A, FK506 neither inhibits HIF-1alpha expression in 8 different cell lines, nor represses the transcriptional activity of HIF-1. Compared with cyclosporine A, FK506 significantly reduced the apoptotic cell death by hypoxia. FK506 could preserve HIF-1 activity in donor organs subjected to hypoxia.

Animals↗

PubMed2006

A domain responsible for HIF-1alpha degradation by YC-1, a novel anticancer agent.

HIF-1alpha is believed to promote tumor growth and metastasis, and many efforts have been made to develop new anticancer agents based on HIF-1alpha inhibition. YC-1 is a widely used HIF-1alpha inhibitor both in vitro and in vivo, and is being developed as a novel class of anticancer drug. However, little is known about the mechanism by which YC-1 degrades HIF-1alpha. As the first step for understanding the mechanism of action of YC-1, we here identified the HIF-1alpha domain responsible for YC-1-induced protein degradation. YC-1 blocked the HIF-1alpha induction by hypoxia, iron chelation, and proteasomal inhibition and also degraded ectopically expressed HIF-1alpha. In deletion analyses, C-terminal HIF-1alpha was found to be sensitively degraded by YC-1. Using a GFP-fusion method, the YC-1-induced degradation domain was identified as the aa. 720-780 region of HIF-1alpha. We next tested the possible involvement of HDAC7 or OS-9 in YC-1-induced HIF-1alpha degradation. However, their binding to HIF-1alpha was not affected by YC-1, suggesting that they are not involved in the YC-1 action. It is also suggested that YC-1 targets a novel pathway regulating HIF-1alpha stability.

Antineoplastic Agents↗

PubMed2005

Amphotericin B blunts erythropoietin response to hypoxia by reinforcing FIH-mediated repression of HIF-1.

Amphotericin B (AmB) is widely used for treating severe systemic fungal infections. However, long-term AmB treatment is invariably associated with adverse effects such as anemia. The erythropoietin (EPO) suppression by AmB has been proposed to contribute to the development of anemia. However, the mechanism whereby EPO is suppressed remains obscure. In this study, we investigated the possibility that AmB inhibits the transcription of the EPO gene by inactivating HIF-1, which is a known key transcription factor and regulator of EPO expression. EPO mRNA levels were markedly attenuated by AmB treatment both in rat kidneys and in Hep3B cells. AmB inactivated the transcriptional activity of HIF-1alpha, but did not affect the expression or localization of HIF-1 subunits. Moreover, AmB was found to specifically repress the C-terminal transactivation domain (CAD) of HIF-1alpha, and this repression by AmB required Asn803, a target site of the factor-inhibiting HIF-1 (FIH); moreover, this repressive effect was reversed by FIH inhibitors. Furthermore, AmB stimulated CAD-FIH interaction and inhibited the p300 recruitment by CAD. We propose that this mechanism underlies the unexplained anemia associated with AmB therapy.

Amphotericin B↗

PubMed2004

New anticancer strategies targeting HIF-1.

Hypoxia-inducible factor-1 (HIF-1), which is present at high levels in human tumors, plays crucial roles in tumor promotion by up-regulating its target genes, which are involved in anaerobic energy metabolism, angiogenesis, cell survival, cell invasion, and drug resistance. Therefore, it is apparent that the inhibition of HIF-1 activity may be a strategy for treating cancer. Recently, many efforts to develop new HIF-1-targeting agents have been made by both academic and pharmaceutical industry laboratories. The future success of these efforts will be a new class of HIF-1-targeting anticancer agents, which would improve the prognoses of many cancer patients. This review focuses on the potential of HIF-1 as a target molecule for anticancer therapy, and on possible strategies to inhibit HIF-1 activity. In addition, we introduce YC-1 as a new anti-HIF-1, anticancer agent. Although YC-1 was originally developed as a potential therapeutic agent for thrombosis and hypertension, recent studies demonstrated that YC-1 suppressed HIF-1 activity and vascular endothelial growth factor expression in cancer cells. Moreover, it halted tumor growth in immunodeficient mice without serious toxicity during the treatment period. Thus, we propose that YC-1 is a good lead compound for the development of new anti-HIF-1, anticancer agents.

Adaptation, Physiological↗

PubMed2004

Versatile pharmacological actions of YC-1: anti-platelet to anticancer.

Since the first article on YC-1 was published in 1994, it has been popularly used as a pharmacological tool to activate soluble guanylate cyclase and to increase cyclic GMP levels in cultured cells or isolated tissues. In terms of the pharmacological actions of YC-1, previous studies tend to be limited to it inhibition of platelet aggregation and vascular concentration. However, recent studies have demonstrated that YC-1 has versatile pharmacological effects other than the anti-platelet and vasodilatory effects. In particular, two recent reports suggest that YC-1 could be developed as a new class of anticancer agent for rapidly growing solid tumors, because it inhibits hypoxia-inducible factor 1 (HIF-1) activity, and has been reported to halt tumor growth in vivo. We here review the cyclic GMP-dependent and independent pharmacological actions of YC-1, and its anti-HIF-1, anticancer effect.

Animals↗

PubMed2004

Spontaneous generation of reactive oxygen species in the mixture of cyanide and glycerol.

Reactive oxygen species are involved in tumor promotion or apoptosis. In assaying prooxidant or antioxidant activities, cyanide has been commonly used as an inhibitor of mitochondrial oxidases, peroxidases, or Cu,Zn-superoxide dismutase, which have an influence on intracellular levels of reactive oxygen species. It has also been used to chemically mimic hypoxia. On the other hand, glycerol has been widely used as a stabilizer of various enzymes. In particular, glycerol is required to maintain the enzymatic activities of membrane-bound NAD(P)H oxidases extracted from surrounding phospholipids. Since both cyanide and glycerol are relatively inert, they have been used concomitantly regardless of any mutual interference. In this study, we demonstrate that a mixture of glycerol and cyanide reduced cytochrome c and nitroblue tetrazolium, both of which are superoxide anion indicators. The mixture also enhanced the production of superoxide anion in the presence of redox-cycling compounds. Superoxide production by the mixture was confirmed by electron spin resonance spectra. Moreover, the mixture induced lipid peroxidation and hemolysis in human erythrocytes. These results suggest that cyanide and glycerol should be used carefully in reaction systems used to measure superoxide production or antioxidant activity. However, sucrose and sodium azide in combination do not produce such artifacts and thus may be used as an alternative.

Cyanides↗

PubMed2003

Phorbol ester stimulates the nonhypoxic induction of a novel hypoxia-inducible factor 1alpha isoform: implications for tumor promotion.

Hypoxia-inducible factor-1 (HIF-1), which is present at higher levels in human tumors, plays important roles in tumor promotion. It is composed of HIF-1alpha and HIF-1beta subunits and its activity depends on the amount of HIF-1alpha, which is tightly controlled by cellular oxygen tension. In addition to hypoxia, various nonhypoxic stimuli can stabilize HIF-1alpha in tumor cells, implying that both hypoxic and nonhypoxic stimuli contribute to the overexpression of HIF-1alpha in tumors. On the other hand, phorbol esters such as phorbol-12-myristate-13-acetate (PMA) are known to be potent tumor promoters. Here, we identified a novel HIF-1alpha isoform, which is regulated primarily by PMA. The variant mRNA lacks exon 11 and produces a 785-amino acid isoform (HIF-1alpha(785)) without altering the reading frame and therefore the COOH-terminal transcriptional activity. HIF-1alpha(785) is induced markedly by PMA and heat shock, the latter of which is also known to induce HIF-1alpha. HIF-1alpha(785) escapes from lysine acetylation because of the loss of Lys(532) and was stabilized under normoxic conditions. Its expression was blocked by reducing agents and by a mitogen-activated protein/extracellular signal-regulated kinase-1 inhibitor and enhanced by hydrogen peroxide. In addition, HIF-1alpha(785) overexpression strikingly enhanced tumor growth in vivo. These results suggest that HIF-1alpha(785) is induced by PMA under normoxic conditions via a redox-dependent mitogen-activated protein/extracellular signal-regulated kinase-1 pathway and that it plays an important role in tumor promotion.

Alternative Splicing↗

PubMed2003

YC-1: a potential anticancer drug targeting hypoxia-inducible factor 1.

BACKGROUND: Hypoxia-inducible factor 1 alpha (HIF-1alpha), a component of HIF-1, is expressed in human tumors and renders cells able to survive and grow under hypoxic (low-oxygen) conditions. YC-1, 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole, an agent developed for circulatory disorders that inhibits platelet aggregation and vascular contraction, inhibits HIF-1 activity in vitro. We tested whether YC-1 inhibits HIF-1 and tumor growth in vivo. METHODS: Hep3B hepatoma, NCI-H87 stomach carcinoma, Caki-1 renal carcinoma, SiHa cervical carcinoma, and SK-N-MC neuroblastoma cells were grown as xenografts in immunodeficient mice (69 mice total). After the tumors were 100-150 mm(3), mice received daily intraperitoneal injections of vehicle or YC-1 (30 microg/g) for 2 weeks. HIF-1 alpha protein levels and vascularity in tumors were assessed by immunohistochemistry, and the expression of HIF-1-inducible genes (vascular endothelial growth factor, aldolase, and enolase) was assessed by reverse transcription-polymerase chain reaction. All statistical tests were two-sided. RESULTS: Compared with tumors from vehicle-treated mice, tumors from YC-1-treated mice were statistically significantly smaller (P<.01 for all comparisons), expressed lower levels of HIF-1 alpha (P<.01 for all comparisons), were less vascularized (P<.01 for all comparisons), and expressed lower levels of HIF-1-inducible genes, regardless of tumor type. CONCLUSIONS: The inhibition of HIF-1 alpha activity in tumors from YC-1-treated mice is associated with blocked angiogenesis and an inhibition of tumor growth. YC-1 has the potential to become the first antiangiogenic anticancer agent to target HIF-1 alpha.

Angiogenesis Inhibitors↗